Next to cardiovascular disease, cancer is one of the most significant health conditions worldwide that accounts for approximately one in four deaths. In the United States alone, health costs are estimated to run into the hundreds of billions of dollars per annum, with around a hundred billion dollars in direct expenditures currently. This expenditure is estimated to be up to US$207 billion by 2020. The incidence of cancer is widely expected to increase as the population ages worldwide, further augmenting the impact of this spectrum of diseases. The current treatment regimens for cancer, established in the 1970s and 1980s, have not changed dramatically. These treatments, which include surgery, radiotherapy and chemotherapy, and other modalities including newer targeted therapies, have shown limited overall survival benefit when utilised in more advanced stage cancers since, among other things, these therapies primarily target the tumour bulk rather than cancer stem cells, which are thought to drive tumourigenesis.
Conventional cancer diagnosis and therapies to date have attempted to selectively detect and eradicate neoplastic cells that are largely fast-growing (i.e., cells that form the tumour bulk). Standard cancer treatment regimens have often been largely designed to the deliver the highest dose of radiation and/or administer chemotherapeutic agent without undue toxicity, i.e., often referred to as the “maximum tolerated dose” (MTD) or “no observed adverse effect level” (NOAEL). Chemotherapy is often added to radiotherapy to improve cancer control, at the expense of increased toxicities. Many conventional cancer chemotherapies (e.g., alkylating agents such as cyclophosphamide; antimetabolites such as 5-Fluorouracil; plant alkaloids such as vincristine) and conventional radiation therapies exert their toxic effects on cancer cells largely by interfering with cellular mechanisms involved in cell growth and DNA replication. Chemotherapy protocols also often involve administration of a combination of chemotherapeutic agents in an attempt to increase the efficacy of the treatment. Despite the availability of a large variety of chemotherapeutic agents, these therapies have many limitations. For example, chemotherapeutic agents are notoriously toxic due to non-specific effects on fast-growing cells whether normal or malignant. For example, chemotherapeutic agents cause significant, and often serious toxicities, including bone marrow depression, immunosuppression, gastrointestinal distress, etc.
Other types of traditional cancer therapies include surgery, hormonal therapy, immunotherapy, epigenetic therapy, anti-angiogenesis therapy, targeted therapy (e.g., therapy directed to a cancer target with agents such as Gleevec® and other tyrosine kinase inhibitors, Velcade®, Sutent® etc.), and radiation therapy to eradicate neoplastic cells in a patient. All of these approaches, often in combination, can pose significant drawbacks for the patient including a lack of efficacy, toxicity and loss of quality of life. Accordingly, new and more effective therapies and/or regimens for improving the long-term prospect including survival and reduced side effects of treatment of cancer patients are needed.
Cancer stem cells comprise a unique subpopulation (typically ˜0.1-10%) of a tumour that, relative to the remaining 90% or so of the tumour (i.e., the tumour bulk), are more tumourigenic, relatively more slow-growing or quiescent, and often more chemotherapy and/or radiotherapy resistant than the tumour cells. Given that conventional therapies and regimens have, in large part, been designed to attack rapidly proliferating cells (i.e., those cancer cells that comprise the tumour bulk), cancer stem cells which are often slow-growing are relatively more resistant than faster growing tumour cells to conventional therapies and regimens. Furthermore, cancer stem cells may possess other features that endow them with chemo-resistance such as multi-drug resistance, and develop and/or enhance anti-apoptotic pathways. These features would constitute a key reason for the failure of standard cancer treatments to ensure long-term benefit in most patients especially those with more advanced-stage cancers (i.e., the failure to adequately target and eradicate cancer stem cells). In some instances, a cancer stem cell(s) is the founding cell of a tumour (i.e., it is a progenitor giving rise to the cancer cells that comprise the tumour bulk).
Two models of cancer stem cell proliferation have been proposed. The stochastic model postulates that oncogenic mutations occur randomly in normal cells and that every cell within a tumour has a low but equal likelihood of re-initiating a tumour. In contrast, the cancer stem cell model posits that tumours arise from a small, phenotypically distinct subset of cancer cells that give rise to the heterogeneous cell lineages observed in a tumour.
Cancer stem cells have several properties that distinguish them from the remainder of the cancer cell population. Most importantly, they undergo asymmetrical cell division, a unique type of cell division in which one offspring cell remain identical to the parent cell, while the other differentiates. In normal adult tissues, self-renewal is displayed exclusively by adult stem cells. Like embryonic stem cells, cancer stem cells sit on top of the tumour cell hierarchy and can respond to stimuli to generate cells further along the differentiation spectrum, albeit in an aberrant manner. Cancer stem cells are also resistant to chemotherapy and radiotherapy, which could explain why conventional treatments are ineffective in curing cancer and relapse occurs in the generally more aggressive forms. Moreover, some cancer stem cells are relatively quiescent shielding them from drugs that target highly proliferating cells. Finally, cancer stem cells can result in metastasis in cancers.
Cancer stem cells have been identified in a large variety of cancer types. For example, leukaemia cells bearing the specific phenotype CD34+CD38− (comprising <1% of a given leukaemia), unlike the remaining 99+% of the leukaemia bulk, were able to recapitulate the leukaemia from when it is derived when transferred into immunodeficient mice (Bonnet et al. (1997) Nat Med 3:730-737). That is, these cancer stem cells are found as <1 in 10,000 leukaemia cells, yet this low frequency population is able to initiate and serially transfer a human leukaemia with the same histologic phenotype as in the original tumour into severe combined immunodeficiency/non-obese diabetic (NOD/SCID) mice.
Similar studies involving cancer stem cells isolated from, for example, human breast cancer (CD44+CD24low lin; Al-Hajj et al. (2003) Proc Nat. Acad. Sci USA 100:3983-3988), human acute lymphoblastic leukaemia (CD34+CD10−, CC34+CD19−; Cox et al. (2004) Blood 104(19):2919-2925), and multiple myeloma (CD138−; Matsui et al. (2004) Blood 103(6):2332) have all been shown to have increased tumourigenic potential in recapitulation studies in mice.
Since conventional cancer therapies target rapidly proliferating cells (i.e., cells that form the tumour bulk) these treatments are believed to be relatively ineffective at targeting and impairing cancer stem cells. In fact, cancer stem cells, including leukaemia stem cells, have been shown to be relatively resistant to conventional chemotherapeutic agents (e.g., Ara-C, Daunorubicin) as well as newer targeted therapies (e.g., Gleevec®, Velcade®). For example, leukaemic stem cells are relatively slow-growing or quiescent, express multi-drug resistance genes, and utilise other anti-apoptotic mechanisms, features which contribute to their chemo-resistance. Further, by virtue of their chemo-resistance, cancer stem cells may contribute to treatment failure, and may also persist following treatment or recur at a later date following apparent initial clinical remission.
Targeting cancer stem cells is expected to provide for improved long-term outcomes for cancer patients. Accordingly, a need exists to provide new therapeutic agents and/or treatments designed to target cancer stem cells to achieve more successful therapeutic outcomes. The present invention seeks to address this problem.